It is now firmly established that the impaired ability of cancer cells to undergo apoptosis plays a major role in the resistance of cancer cells to chemotherapy or radiation and for the failure of current anti-cancer drugs. Hence, future efforts toward designing new molecular-targeted therapies must include novel strategies that specifically target the resistance of cancer cells to apoptosis. Bcl-2 and Bcl-xL proteins represent exciting anti-apoptotic molecular targets for designing new anti-cancer drugs by aiming at overcoming resistance of cancer cells to apoptosis. This NCDDG application proposes to design and develop novel nonpeptidic, small-molecule inhibitors of Bcl-2 and Bcl-xL proteins as a new class of anti-cancer drugs through a contemporary, multidisciplinary and integrated drug discovery approach. Our overall hypothesis is that smallmolecule inhibitors of Bcl-2 and Bcl-xL will overcome apoptosis-resistance of cancer cells with high levels of Bcl-2/Bcl-xL overexpression. Such small-molecule inhibitors will also have a high selectivity since most normal cells have low levels of Bcl-2/Bcl-xL proteins and do not depend upon Bcl-2/Bcl-xL for survival. This application consists of three inter-dependent and integrated research Programs: 1. Computational structure-based design, chemical synthesis, biochemical characterization and molecular mechanism of action studies (Shaomeng Wang, Ph.D. University of Michigan) 2. Determination of high-resolution experimental three-dimensional structures of small-molecule inhibitors in complex with Bcl-2 and Bcl-xL by X-ray crystallography and by nuclear magnetic resonance (NMR) methods;(Jeanne Stuckey, Ph.D. University of Michigan and YorkTomita, Ph.D. Georgetown University) 3. The therapeutic potential, pharmacology, and toxicity of promising small-molecule inhibitors in preclinical models of human hormone-refractory prostate cancer. (Kenneth Pienta, M.D. University of Michigan) The overall goal of this NCDDG drug discovery program is to bring a highly potent and promising smallmolecule inhibitor of Bcl-2 and Bcl-xL proteins for advanced preclinical development in anticipation of an IND filing with a commercial partner. It is predicted that a potent small-molecule inhibitor will not only be useful for the treatment of hormone refractory prostate cancer but also for many other types of human cancer, in which Bcl-2 and/or Bcl-xL is highly overexpressed and for which traditional therapy has failed.